9 February 2006. The prescription of multiple antipsychotic drugs, or "polypharmacy," is a common practice in the treatment of schizophrenia, particularly in patients who fail to improve after attempts with several different drugs. The hope is that drugs with slightly different profiles—differential receptor activities and effectiveness in different symptom domains—might augment each other. However, most of this prescribing is being done on sparse evidence for its effectiveness and with concerns about the additive side effects of these expensive drugs, especially on metabolic systems (see SRF related news story on the CATIE trial).

A new study published February 2, 2006, in the New England Journal of Medicine casts doubts on this practice, at least with two drugs, in one particular subgroup of patients. William Honer of the University of British Columbia, Vancouver, and colleagues at a number of institutions report that in a multicenter, international trial, the addition of risperidone to clozapine produced no benefits over placebo in treatment-resistant schizophrenia.

This particular polypharmacy strategy has a logic, namely that risperidone (Risperdal, Janssen), which occupies a high percentage of dopamine D2 receptors at clinical doses, might occupy any D2 receptors left vacant by clozapine (Clozaril, Novartis), which occupies a lower percentage of D2 receptors (Kapur et al., 1999). Binding affinity to D2 receptors has been shown to correlate with antipsychotic drug effectiveness, particularly for psychosis and other positive symptoms. There are also hints that risperidone might have greater benefits for working memory (Woodward et al., 2005). However, previous, smaller studies of the risperidone/clozapine combination have been contradictory on the value of this approach.

The researchers randomized 68 patients in Canada, Germany, China, and the United Kingdom to receive either risperidone (3 mg/day) or placebo on top of clozapine in a double-blind design for 8 weeks. The manufacturer of risperidone supplied the medication for the trial, but was not otherwise involved in it, according to the authors. Patients were, on average, in their late thirties, with a duration of illness of about 15 years. They had tried, on average, three antipsychotic drugs over the previous 5 years, ending up on clozapine at an average dose of 490 mg per day.

Honer and colleagues found that both groups improved significantly from baseline on a battery of measures, including the Positive and Negative Syndrome Scale (PANSS) and neurocognitive tests, but there was no benefit of risperidone over placebo. The authors report that nine of 34 patients in the placebo group improved on PANSS scores, versus six of 34 in the risperidone group (p = 0.038). Indeed, the placebo-treated patients had a slight improvement in working memory over the risperidone group (p = 0.02). Fasting blood glucose levels increased significantly more in the risperidone-treated group, though the authors emphasize that this finding should be viewed as preliminary.

In an editorial accompanying the article, John Davis of the University of Illinois, Chicago, and the Maryland Psychiatric Research Center in Baltimore, cautions that too low a dose of risperidone may have been used. Davis noted that the previous, industry-funded trials that showed a benefit of this polypharmacy had found that daily doses of over 4 mg were more effective than lower doses. "Nonetheless, the Honer trial was carefully conducted, and its negative findings introduce palpable doubt about the efficacy of augmentation therapy in refractory schizophrenia. Given the contradictory results among these studies, more industry-funded and independently funded trials are needed," Davis writes. This editorial is also worth reading for Davis's thoughts on antipsychotic prescribing in general, and the CATIE trial in particular.—Hakon Heimer.

Evaluating the effect of adding risperidone to clozapine is an example of clinical practice getting out ahead of evidence and theory. It has become common practice, so we need to know the answer. The combination surely will add adverse effects, but what hypothesis supports the notion of increased efficacy? Clozapine has superior efficacy for psychosis in treatment-resistant patients and low occupancy (fast on/off) at the dopamine 2 receptor. Is this important for diminished motor adverse effects or for superior efficacy? If so, adding risperidone will terminate this advantage. I think this may be the case for adverse effects, but we tested the partial occupancy hypothesis and the D2/5HT ratio hypothesis for clozapine (Carpenter et al., 1998) and found that full D2 occupancy did not interfere with clozapine superiority. But in this analysis, we found no evidence that being on a drug with high affinity for the D2 receptor combined with clozapine gave any efficacy advantage and recommended against the practice.

To reason in the other direction, it is clear that risperidone has its best benefit/adverse effect profile at low doses. Combining risperidone with another antipsychotic could move that profile in an unfavorable direction.

But clinicians are stuck. In most patients, no matter what the pharmacotherapy, response is incomplete. It is understandable that doctors try “harder,” and increasing dose and polypharmacy seem the only way. When only first-generation drugs were available, this routinely lead to excessive doses with more adverse effects, poorer adherence, and no evidence for better efficacy. Are we now repeating this mistake with polypharmacy? This clozapine/risperidone report is well done, and the failure to observe an advantage for the combination should be a decisive influence on this common practice.

The paper by Honer et al., which reported a lack of benefit from augmentation of clozapine by risperidone in patients with schizophrenia who were partial responders to clozapine, is consistent with our previous report which had the same design but was of somewhat shorter duration (Anil Yagcioglu et al., 2005), with the exception that we found that improvement in psychopathology after the addition of placebo was superior to risperidone. A second paper from our double-blind, randomized trial has been submitted which showed that improvement in cognition with placebo was often, but not always, greater than that with risperidone as well. Honer et al. explicitly stated that their results were consistent with ours. We proposed, based upon my hypothesis that more potent blockade of 5-HT2A than D2 receptors contributed to the beneficial effects of clozapine (Meltzer et al., 1989), that the reason for the superior response to placebo in our trial was that risperidone, by adding D2 receptor blockade to clozapine, interfered with the beneficial effects of being part of a clinical study with its increased clinical contact and supportive nature. The results of our study and that of Honer contrast with a third study (Josaissen et al., 2005), which found risperidone addition improved psychopathology more than placebo.

The New England Journal of Medicine editorial from John M. Davis is a very disappointing commentary on this important confirmation of our research in a key area because it has a number of serious errors in fact and gratuitous criticism of industry-funded studies which, at least in this case, are easily refutable. Davis stated that our study and that of Josiassen et al. were industry-funded, as contrasted with the Honer et al. study, which was funded by the Stanley Medical Research Foundation, of which Davis has been a long-time adviser. The implication is clear that the industry-funded studies are biased. Davis then continues his effort to raise doubt about industry-funded studies by contrasting the results of his several meta-analyses of industry-funded clinical trials, which found advantages of atypical over typical antipsychotic drugs, with that of the NIMH-funded CATIE study, which did not (Lieberman et al., 2005).

In fact, our study was clearly marked as having been funded by the Stanley Medical Research Foundation, the William K. Warren Medical Research Foundation, and the Janssen Pharmaceutical Company, manufacturer of risperidone. The Josaissen study was industry-supported. Instead of evaluating the three studies for their merits, or even reading the paper carefully (in the case of our study), Davis would have us doubt their validity because they were industry-supported. This is unacceptable in my view. His call for more industry and non-industry studies is a smoke screen for his real message, that industry-funded studies are biased. I and my coauthors can vouch for the fact that none of the three funders of our pioneering research exerted the least influence on the design, performance, or write-up of our work. Janssen was informed of the results of the study as called for in our contract and made no effort, nor should it have, to restrain or modify the message. This, in fact, has been consistent with my entire experience with major pharma and biotech companies. If Professor Davis has had more negative experiences with industry in this regard, he should make them public. As it is, he offers incorrect information to raise doubts about industry-funded research at a time when it is already under attack in the area of clinical trials and when continued investment on its part in clinical research in psychiatry is urgently needed, in my view. What we need is more thoughtful consideration of the merits and shortcomings of all clinical trials regardless of funding source. The clinical investigators and funder of the CATIE trial are now finding that merely because their study was government-funded, it is not being taken by many as the last word in informing us about antipsychotic drug treatment in schizophrenia.

Our paper (Honer et al., 2006) and the associated editorial by Dr. John M. Davis (Davis, 2006) concerning augmentation of risperidone with clozapine drew some commentary in this Forum, and recently, three letters to the Editor of the New England Journal of Medicine. The April 27 issue of the NEJM also includes our response, and a response from Dr. Davis. The first of the letters, from Grass and colleagues (Grass et al., 2006) concerns the broader issues of the confidence with which we can conclude that risperidone augmentation of clozapine offers no benefit, and the degree to which the results of this approach to antipsychotic polypharmacy can be generalized to other combinations of antipsychotic drugs. Basically, our conclusion in the paper is that the difference between risperidone and placebo augmentation of clozapine is unlikely to be associated with a moderate-to-large effect size, such as would be observed with switching a group of patients from typical antipsychotics to clozapine. Smaller differences cannot be excluded. However, as clarified by Dr. Davis in the recent issue, one of the two previous, smaller placebo-controlled studies showed relative benefit for placebo versus risperidone augmentation, at least for positive symptoms (Anil Yagcioglu et al., 2005). The NEJM letters from Meltzer and colleagues (Meltzer et al., 2006) and from Gerson (Gerson, 2006) concern the Davis editorial which accompanied our paper. Dr. Meltzer’s concerns about the editorial are also presented in his commentary in the Forum, and Dr. Davis has graciously apologized for his errors in the current response in the Journal, and clarified that monitoring of white cell counts provides a safe approach for patients taking this medication.

We still face the broader issue of antipsychotic polypharmacy, which appears reasonably prevalent despite a very small evidence base. Our trial was initially designed with the hope that risperidone, being a high-affinity dopamine D2 antagonist, would be an optimum drug to augment the low D2 affinity of clozapine. This was not the case, and strictly speaking our results cannot be generalized beyond this combination of medications. Much larger studies would be needed if a non-inferiority design were to be used. For example, subjects currently treated with antipsychotic polypharmacy could be randomized to continuation or to substitution with placebo for all but one antipsychotic drug. A preliminary, uncontrolled study indicated this strategy was successful in most, but not all cases (Suzuki et al., 2004). Perhaps new findings concerning the consequences of antipsychotic polypharmacy for cognitive function (Kawai et al., 2006) and the economic costs (Stahl and Grady, 2006) will also contribute to improving evidence-based practice.

The Lieberman et al. CATIE study is a landmark large-scale clinical trial of antipsychotic drug therapy and will generate considerable discussion in the coming months. It offers important insights about real-world treatment of individuals with the diagnosis of schizophrenia, in the sense of typical practices in clinics around the country and the clinical experience of many practitioners. It probably comes as no surprise that the response to available antipsychotic agents is suboptimal and that differences between drugs are not dramatic in many cases.

One of the questions that comes to my mind about the results is whether and to what degree they are generalizable. Do the results of this study accurately characterize the effects of these drugs across the spectrum of patients with chronic schizophrenia who are treated with them? In other words, are the patients in the CATIE trial representative of the patients with chronic schizophrenia who are in need of these medications? I believe there are several indicators to suggest that they may not be. First, of the subjects in this trial, most of whom (75 percent) were male, 40 percent had been or were married. Second, the mean age at first antipsychotic treatment was 26 years. Third, 30 percent of the subjects were on no medication when they entered the trial. These are all somewhat atypical characteristics in my experience, especially for a predominantly male sample.

In the NIMH schizophrenia genetic study that I direct, we have extensively evaluated over 600 subjects with schizophrenia from around the country. In our sample, the mean age at first antipsychotic treatment is 21 and the ever-married rate is 15 percent, and our sample is one-third female. Moreover, less than 10 percent of our sample is unmedicated at the time that they are evaluated. The finding that a mean dose of 20 mg of perphenazine was as effective as other medications also is somewhat surprising in my experience, as having used this drug for many years, I have rarely seen chronic, actively symptomatic patients respond well without dosing around 32 milligrams and above. Is it possible that the CATIE trial inadvertently enrolled patients more in the schizophrenia spectrum end of the distribution of patients receiving these drugs who may tend not to show as clear benefit? Or maybe the size and breadth of the CATIE trial obscured the signal from the more classic patient with schizophrenia for whom antipsychotic treatment is essential.

It will be interesting to see whether other academic schizophrenia centers concur with the demographics of my experience as noted above or those of CATIE. Multicenter studies—and CATIE involved 57 centers each contributing relatively small samples over a 2-year period—are susceptible to dilution effects and to the possibility that the sample is clinically "noisy." It will be interesting to see, when data analyses from the next stages appear, whether differences are found in the results from different centers who participated in the trial. Will CATIE have told the story of how these drugs work in patients who receive them, or will it have failed to identify the signal from the noise?

I also have not seen the response at that dose of perphenazine and even the atypical antipsychotics in chronic schizophrenics. In fact, the only medication that seemed to have an adequate "real-life" dose was olanzapine.

It seems that the doses used are not equivalent,
and the researchers have used somewhat lower doses of perphenazine and risperidone (in favor of olanzapine). Thus, it is obvious that perphenazine and risperidone have showed smaller efficacy.

There is evidence that the Chinese traditional medicines may be an alternative approach in the treatment of schizophrenia. Our recent studies indicate that the extraction of gingko biloba may increase the effectiveness of antipsychotic drugs, but reduce their side effects. This finding may provide a new clue to develop a novel therapeutic drug for treatment of schizophrenia.

Reply to Dr. Weinberger's questions about the generalizability of the CATIE sample, by
Marvin Swartz, for the CATIE investigators
As CATIE investigators, we have been mindful of concerns about the generalizability of the CATIE sample. In response to a similar concern, our colleague Jeffrey Swanson at Duke compared CATIE participants to a quasi-random sample of 1,413 patients enrolled in the Schizophrenia Care and Assessment Program (SCAP), an observational, non-interventional study of schizophrenia treatment in usual care settings in the United States. The two samples were similar in demographic characteristics, e.g., gender (70 percent male in SCAP, 74 percent male in CATIE), age (mean age = 43 years in SCAP, mean age = 41 years in CATIE), and education (36 percent of SCAP participants had a high school education and 28 percent attended college; in CATIE these percentages were 35 percent and 39 percent, respectively). The CATIE study had a lower proportion of participants from racial minority backgrounds (40 percent vs. 54 percent).
The samples also resembled each other in clinical characteristics. Nearly one-third of the patients in both studies had recently been hospitalized. The CATIE sample had slightly higher average scores on psychotic symptom severity than the SCAP patients (mean PANSS total score = 75 vs. 71), and also slightly higher scores on functioning and quality of life (mean Heinrichs-Carpenter QLS score = 63 vs. 57) (Haya Ascher-Svanum, Ph.D., Senior Research Scientist, Eli Lilly and Company; personal communication). These similarities provide some confidence that CATIE’s RCT design did not result in a biased selection of patients.

The antipsychotic drugs mainly treat psychosis (in contrast to cognition impairments and primary negative symptoms). In the CATIE study, the drugs tested share the same mechanism of action (D2 antagonism). Clozapine aside, the second-generation drugs (SGA) have not established superior efficacy over first-generation drugs (FGA). The FDA has granted no such claim, and the Cochrane reviews do not support superior antipsychotic efficacy. The appearance of superiority, including the terrific organization of data in the Davis meta-analyses, may be extensively based on last observation carried forward, excessive dose of the FGA, failure to pretreat with anti-parkinsonian drugs, sponsor bias, and a number of other methodological problems including the fact that most study subjects are doing poorly on FGA when recruited into comparative studies. "Atypical antipsychotic" means only low extrapyramidal symptoms at therapeutic dosing. In this regard, the CATIE findings are not surprising, but simply point to the considerable shortfall in effectiveness associated with current treatments. The drugs will vary considerably along side effect liabilities, and matching patient to side effect profile is the key to individualizing drug choice at the moment.

As to time on drug, there was not a long-acting depot arm to the study, and this method should probably be considered in substantially more patients than is the practice in the U.S. Olanzapine did a little better on the time on drug measure, and risperidone was second. This may relate to the fact that these were the two most common drugs used at study onset, so more patients with known tolerability to these drugs began the trial. In any case, concern with weight and the metabolic syndrome will drastically cut the time on drug for olanzapine in current practice.

It is almost impossible to have a level playing field in comparative drug studies, since optimal dosing and individualized dosing parameters are simply little known with most antipsychotic drugs. In this regard, we don't know if quetiapine and ziprasidone would have done better at higher dose; or if risperidone being yoked to olanzapine led to suboptimal dosing in many cases. In Rosenheck's JAMA report, he observed that pretreatment with an anti-parkinsonian drug led to similar effectiveness comparing olanzapine with haloperidol. Would perphenazine have been even better with anti-cholinergic pretreatment?

In my view, this is a critically important study in that it reasonably represents an effectiveness study in typical settings [probably more representative than the Weinberger data set (see Weinberger commentary)] without sponsor bias. As such, it has succeeded in calling public attention to the relative lack of progress associated with "me-too" dopamine blocking antipsychotic drugs. This conclusion is reinforced by the U.K. study reported by Peter Jones at the ICOSR where SGA did not beat FGA on the primary endpoint (quality of life) or on many secondary measures. Another head-on comparison study with public support.

My hope is that industry will devote discovery resources to the challenging problems of novel treatments with new molecular targets addressing problems with impaired cognition and primary negative psychopathology. Refining antipsychotic drugs has not advanced therapeutics much since the introduction of chlorpromazine. Reducing the neuroleptic adverse effects of FGA is a real advance, especially considering the excessive dosing. But significant new liabilities are associated with some of the SGA. We now need to meet the efficacy challenge for the components of schizophrenia that mainly cause poor functional outcomes.

Dr. Swarz's comment providing data from the SCAP study is helpful in confirming that CATIE patients are similar in many phenomenological respects to other patients in schizophrenia treatment programs. Indeed, in terms of PANSS ratings, sex ratios, age at enrollment in the study, and history of recent hospitalizations, CATIE patients are not substantially different from patients we see at the NIH in Bethesda, Maryland and we saw when our program was located at St. Elizabeths Hospital in Washington, D.C. In my comment, I asked specifically about three CATIE characteristics that seemed atypical to me: age at first antipsychotic treatment (26), precentage of patients who were or had been married (40%), and percentage of patients who were unmedicated at the time they volunteered for the study (30%). It would enlighten this discussion if Dr. Swarz would report these data from the SCAP study.

It would be interesting to learn from Dr. Swartz and the CATIE investigators (a) the age at first antipsychotic treatment, (b) the percentage of patients who were or had been married, and (c) the percentage of patients who were unmedicated at the time they volunteered for the study in the SCAP sample. I suspect these three variables, if available, will more closely resemble those of the CATIE trial sample than the CBDB sibling study sample.

Dr. Weinberger has suggested that the CATIE trial inadvertently enrolled patients more in the schizophrenia spectrum end of the distribution, or maybe the size and breadth of the CATIE trial obscured the signal from the more classic patient with schizophrenia, so the results may not be generalizable. I suspect that differences in criteria for recruitment and retention between the CBDB sibling study and the CATIE study explain the differences among the demographic variables of the samples.

The clinical characteristics of the CBDB sibling study sample are what one would expect in a study whose purpose is to find associations between genetic variation and neuroimaging/neuropsychological phenotypes, among affected and unaffected family members. The usual patient included in the CBDB sample probably: had onset of active symptoms in late adolescence or early adulthood (i.e., high school or college age, before many people marry); was started on medications earlier in life; and had more intact nuclear families (parents, siblings, etc.) than the usual CATIE subject. Patients with later onset of illness or milder symptoms (who are more likely to be or have been married) and who did not start on medications once psychotic symptoms occurred, were less compliant with their medications, and/or had fewer intact family relationships were unlikely to successfully travel to Bethesda and complete two full days of research testing. The CATIE recruitment strategy did not exclude the unusual patient with treatment of symptoms later in adulthood, require intact nuclear family, or require compliance with medications at time of study entry.

The CBDB sample better represents a "textbook case" of schizophrenia. Many patients who do meet DSM-IV criteria for schizophrenia may not be good candidates for a genetics study, but may still have schizophrenia and are appropriate candidates for a large clinical study. This would suggest that the findings can be generalized to other groups of patients with the illness, though perhaps not the "classic" cases of schizophrenia gathered in the CBDB study.

Reply to comment by Johann Samuhanand
To our best knowledge, there is no published evidence that gingko biloba could be useful in reducing the side effects of clozapine and other atypicals. However, using the same group of patients with schizophrenia as we reported previously (Zhang et al., 2001), our recent study has shown that chronic patients with schizophrenia demonstrated significantly lower CD3+, CD4+, and IL-2 secreting cells, together with CD4/CD8 ratio, than did healthy controls at baseline. After a 12-week treatment, EGb added to haloperidol treatment increased the initially low peripheral CD3+, CD4+, and IL-2 secreting cells, together with CD4/CD8 ratio. There was only a significant increase in CD4+ cells in the placebo plus haloperidol group. These findings suggest that ginkgo biloba may improve the decreased peripheral immune functions in schizophrenia (Zhang et al., 2006).

As we have known, although clozapine is superior over the other drugs in terms of efficacy, it can severely deplete white blood cells, leading to limitations on its use. If gingko biloba may indeed produce beneficial effects on the immune system in schizophrenia, there is a possibility that ginkgo biloba may be useful in reducing the side effects of clozapine, at least in regard to immune function.

On the other hand, a limitation of the design of our previous study (Zhang et al., 2001) is the use of haloperidol as the antipsychotic treatment at a time when atypical antipsychotic drugs are the standard of care. Therefore, a further study is warranted to investigate whether ginkgo biloba shows similar benefits in augmenting the atypical antipsychotics, which already have the capacity to improve the positive and negative symptoms and have better profiles in terms of extrapyramidal side effects.

I recommend this clear and well-written paper for students to understand the basis of the CATIE studies.

I agree with Dr. Weinberger about the variables that could obscure the results in the target population or the schizophrenic population. His remarks about the control conditions or the dissection of the variables in the study are important. The difference between typical and atypical drugs is clear in these data.

New drugs, diferent from the typical and atypical drugs, based on new genetics research and new genetic routes must be developed in order to achieve new successes in the treatment of schizophrenia.

I think that atypical antipsychotics do not mean only low extrapyramidal symptoms at therapeutic doses.
Several studies have demonstrated that atypical drugs(especially olanzapine) are better than typical drugs in important characteristics such as cognitive functioning.

The most important current development of new antipsychotic drugs is focused on two mechanisms, the α7-nicotinic receptor agonists that are good new candidates for the management of the disease (Martin et al., 2004) and, most recently (and I think probably the closest to development), is the one that focuses on glutamatergic neurotransmission (Coyle and Tsai, 2004).

On the other hand, I think that behavioral and cognitive therapy, as well as family support and family management given by a professional in this area of health, are important to ensure an excellent result in schizophrenic patients.

Comment by: Robert FisherSubmitted 24 December 2005
Posted 28 December 2005 I recommend the Primary Papers

[Disclosure: R. Fisher was Study Coordinator, Recruiter, and Diagnostician for the Byerly Group at UT Southwestern CATIE site, the second-largest enrollment site in the study.]

The CATIE study is likely the best designed and implemented research project ever conducted regarding schizophrenia and relevant psychopharmacology. The extensively collected data will have an enormous heuristic value in the study and evaluation of this disorder in all aspects of schizophreinia. I found Drs. Lieberman and McEvoy to be true professionals in this study design.

I believe that the results of the CATIE study indirectly support the core principle of treatment, that is, it should be comprehensive, using a biopsychosocial approach. The large number of dropouts is but one example of the limitations of relying on antipsychotic medication alone in the treatment of schizophrenia. We know that psychosocial treatments enhance compliance and overall outcome. See, for example, the study that my colleagues and I conducted on relapse prevention in schizophrenia, which had a small number of dropouts over 18 months (Herz et al., 2000).